Large scale solid phase peptide synthesis requires consideration of a number of reactor design issues. The resin used is usually a gel resin with a low degree of cross-linking which swells in certain solvents (such as DCM), and shrinks in others (such as methanol). The resin volume tends also to increase with the growth of the peptide chain length. In addition, the resins tend to be fairly soft, and sensitive to physical attrition. Furthermore, the amount of exposure time between the peptide-resin and the solvents and reactants used in the synthesis is often critical. Deprotection of the resin-bound peptide must be complete in order to obtain the highest yield, but the resulting carbocations must not remain in contact with the peptide because of undesirable side-reactions that may occur. Unfortunately, the time required to drain the solution from a resin slurry suspension increases with the depth of the resin bed formed during filtration. Consequently, exposure time of resin-bound peptide to carbocations increases as bed depth increases. As a result, the filtration times for kilogram-scale reactions are far longer than those encountered in bench-scale reactions, so the risk of damage to the peptides due to reactions with carbocations increases with batch size. Larger scale reactors must therefore be designed in such a way as to minimize the filtration time.
Several attempts have been made to overcome the constraints imposed by the resins with tube reactor designs: Verlunder, et al., U.S. Pat. No. 4,192,798 (an industrial-scale HPLC type of reactor); Baru, et al., WO88/909010.6, SU 4117080 (a zero dead volume reactor in which one end of the reactor was allowed to float with the resin); Atherton, et al., JCS Chemical Communications, p. 1151 [1981] (a rigid polymer with macropores); Lapluye and Poisson WO 92/115867 (piston-type reactor with fritted ends); Birr, German Patent No. 2,017,351 and Stepaniuk et al. WO98/34633 ("washing machine" type reactors); and Anderson and Anderson, U.S. Pat. No. 5,186,824 (a centrifugal flooded "hollow rotor" reactor).